Novel Therapeutic Interventions in Rheumatoid Arthritis: This proposal is organized as a training vehicle that reflects a new direction in my interests to combine mechanistic and translational investigation in rheumatoid arthritis. The core of this proposal is the desire to model the effectiveness and feasibility of two novel therapeutic interventions in RA, autologous bone marrow transplantation and gene therapy. Both of these modalities are already being investigated by other researchers and there is widespread, keen clinical interest. I believe that with this work we can, with a careful and judicious application of available information, obtain both useful insight into etiopathogenesis and practical therapeutic utility. We propose to perform this work as outlined in the following two Specific Aims: Specific Aim 1. The treatment of arthritis by immunoablation followed by stepwise immune reconstitution by drug resistance-transduced stem cells. The existent technologies for bone marrow reconstitution, peripheral blood stem cell harvesting, retroviral transduction, and in vivo drug selection will be combined to allow the gradual development of individual bone marrow chimeras. Several strategies for immunoablative conditioning prior to bone marrow reconstitution will be addressed. This approach will be applied to several mouse arthritis models. We believe that information gained from this work should have an immediate impact on the collaborative efforts that we have already begun with transplantation specialists at The University of Pennsylvania to develop strategies for bone marrow transplantation as a treatment for RA and other Autoimmune Diseases. Specific Aim 2. Gene Therapy in Arthritis as an Investigational Tool. We will expand FasL gene transfer work to other models of spontaneous and induced autoimmune arthritis and perform experiments designed to delineate the cells targeted by this intervention. This will confirm prior observations made in the collagen-induced arthritis model, validate the universality of this therapeutic approach in RA and serve to further understand mechanisms at play. We hypothesize that FasL gene transfer will be effective in preventing and ameliorating arthritis regardless of its etiology so long as the disease is mediated by activated synovial cells expressing Fas molecule. This work will allow me to develop new skills and a wider understanding of the usefulness of gene therapy approaches as both a therapeutic modality and an investigational tool.